Thursday, December 19, 2013

Curvularia: human and plant pathogen

By Nathan Kemp

Curvularia species are well known for their ability to cause disease in plants, but they are also able to cause localized infections in all different tissues; as well as systemic, disseminated disease in humans (1). Due to an increased awareness of clinical cases of Curvularia sp.-caused disease, inquiry into the mechanisms of disease as well as the taxonomy of said species has led to the development of tools for treatment and the discovery of beneficial
metabolites that are produced by the organism.

In the past twenty years, fungi have made a large impact on the clinical setting and in genetics. Bacteria and viruses are commonly to blame for most illnesses; until recently, fungus and other eukaryotic pathogens generally took a backseat to
bacteria and viruses in terms of development of treatment and understanding of pathogenesis. As HIV/AIDS has taken hold, those infected are more likely to develop fungal infections due to defective immune systems. Those that are immunocompetent are not necessarily safe either (1,2). Recently, fungal disease has made major mainstream news as a UCLA quarterback was nearly killed by aspergilliosis, a rare and often fatal disease caused by molds (3).

As more and more cases of fungal infection are reported, more time and money are invested into treatment and study of the organisms responsible. Fungi produce a huge amount of known and unknown secondary metabolites and research has led to
more and more discoveries of these compounds (4). Secondary metabolites are compounds that are produced by the organism but are not necessary for its survival. Some are poisonous to other microbes, such as the antibiotic penicillin; others are toxic.

Curvularia is a hyphomycete, or mold fungus that produces conidia, an asexual spore that is pale brown, cylindrical, and slightly curved (1). On agar plates, it produces “suede-like” to downy, brown to black colonies (1). Transmission of Curvularia can occur through inhalation of conidia or through cutaneous inoculation in an area where the skin has been breached (1).

Due to a lack of study, little taxonomic analysis has been done on Curvularia and thus, current clinical methods have relied on phenotypic analysis of the fungi (1). Phenotypic analysis may be faster than genomic identification, such as sequencing of certain genes, but it has numerous drawbacks and is not always appropriate for taxonomic organization. Incorrect identification can lead to improper treatment with antifungals, which in turn can lead to resistance (1). This could lead to poorer clinical outcome. The molecular identity of numerous clinical isolates as well as their antifungal susceptibility has been identified by Cunha et al. recently (1).

The identity of these organisms was determined via its rRNA and the GAPDH gene (1). The rRNA is a nucleic acid that will rarely change from generation to generation, because it is absolutely essential to survival of the organism. The GAPDH gene is referred to as a housekeeping gene, something that each organism has and that exhibits little polymorphism, so it too can help identify strains. Cunha et al. found numerous errors in the identification via phenotype and was able to group species more effectively based on these polymorphisms (1). The more important part with regards to clinical outcome is that they then associated these groups or clades with certain MIC’s, or minimum inhibitory concentrations, of antibiotics. Minimum inhibitory concentrations are the amount of compound, which will begin to inhibit growth of an organism. This allows clinicians to treat infections more effectively.

In order to successfully tackle this new fungal resurgence, we need not only learn to treat the disease but also understand its pathogenesis. This is where animal models come in. Rather than clinical studies, animal models are cost-effective and experiments can be performed in replicates in a controlled environment. One such model for Curvularia has been developed by Paredes et al (2): It is a mouse model that helps with the understanding of the more lethal form of Curvularial disease, disseminated infection. This is when the fungus spreads throughout the body and can affect numerous tissue types. In order to study the
disseminated infection, they injected two drugs, 5-fluorouracil and cyclophosphamide, to suppress the immune system of the mouse (2). Through this model, they were able to quantify differences in virulence of strains of Curvularia sp. and analyze the primary locations of the fungus within the animal. Tissue sections of infected mice showed fungus primarily in the lung and kidney, but some was also found in the brain, spleen, and liver as well (4).

Despite causing disease in mammals and in plants, Curvularia is not entirely a bad guy. As mentioned earlier, fungus is an excellent source of secondary metabolites that can have a variety of functions, and we have very little knowledge of such functions. Not all secondary metabolites are toxins, some may have potential in medicine, such as Curvularol, which was discovered by Honda et al. in 2000 (4). Curvularol does not show antifungal or antibiotic properties, but it is a cell cycle inhibitor (4). These inhibitors could be used to treat uncontrolled growth, i.e. cancer, by arresting the cell cycle. Curvularol was shown to stop cell growth in normal kidney cells from rats, but more importantly, induced morphological reversion of cancerous rat cells (4). Rat cells that were transformed with a Rous Sarcoma Virus (tumorogenic virus) changed from a flat, normal shape to a round shape (4).The changes in cell shape are indicative of abnormal gene expression which can lead to cancerous growth. The cells were then grown in the presence of
curvarol and returned to a normal shape (4). It also inhibited protein synthesis as well as cycloheximide, a potent protein synthesis inhibitor. When protein synthesis is halted, growth arrests, because the cell is no longer able
to make machinery necessary for replication (4).

The emergence of fungal pathogens in the clinical setting has brought about new interest in treatment, taxonomy, pathogenesis, and the study of secondary metabolites in fungi (1,3,4). Curvularia species are fungi that have rarely been studied extensively as a human pathogen, as its presence as a plant pathogen causes crop destruction and
economic damage (1). However, Curvularia is capable of numerous types of localized infection as well as the more serious disseminated infection in humans (1). In order to effectively treat these infections, the various species of Curvularia have been recently grouped based on sequencing and anti fungal susceptibility has been measured (1). A mouse model has also been developed as an effective means to study the disseminated infection and increased study of Curvularia species has led to the discovery of secondary metabolites that are possibly beneficial to humans
rather than just harmful (2,4).

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